Cocaine abuse has reached epidemic proportions in the United States and has emerged as a major cause of life-threatening cardiovascular emergencies. While these emergencies clearly are related to excessive adrenergic stimulation of the cardiovascular system, our understanding of the underlying mechanisms mediating cocaine's sympathomimetic effects is far from complete. The prevailing view is that cocaine blocks the norepinephrine reuptake transporter in peripheral sympathetic nerve terminals, thereby increasing norepinephrine concentrations in the synaptic cleft. However, our work in the past grant cycle challenges the predominance of this mechanism and demonstrates that in cocaine-naive healthy humans: (1) Intranasal cocaine stimulates postganglionic sympathetic nerve activity (SNA), the neural stimulus to norepinephrine release; and (2) Sinoaortic baroreflexes play a pivotal role in buffering this cocaine-induced sympathetic excitation. The interplay between these excitatory and inhibitory neural influences seems to determine the net effect of cocaine on SNA targeted to the human peripheral circulation. We now turn our attention to cocaine abuse. Because the vast majority of cocaine abusers also abuse tobacco, particular attention will be paid to key interactions between the sympathomimetic effects of cocaine and nicotine. Our major new hypothesis is that cocaine greatly amplifies an otherwise subtle sympathomimetic action of nicotine by two separate mechanisms: (1) When administered concomitantly, cocaine and nicotine interact acutely to produce a massive increase in central sympathetic outflow targeted to both the skeletal muscle and cutaneous circulations; and (2) When abused chronically, cocaine accelerates the aging-related decrease in great vessel distensibility, thereby attenuating sinoaortic baroreflexes. The distinctive features of this proposal include the: (1) use of state-of-the-art techniques (microelectrode recordings of SNA; gated cardiac MRI) to test mechanistic hypotheses in conscious humans; (2) focus on modulation of central sympathetic outflow by cocaine, which traditionally has been viewed as a peripherally-acting sympathomimetic; (3) concept of a synergistic interaction between effects of cocaine and nicotine on the reflex control of SNA; and (4) study of chronic cocaine abusers to directly address the clinical importance of our experimental findings. These studies should fill in some important gaps in our understanding of the underlying mechanisms mediating the sympathomimetic actions of cocaine on the human cardiovascular system.